CD47 is a membrane-associated protein also called Integrin Associated Protein (IAP). Integrins are one of adherent cells playing a role in the adhesion of a cell to the extracellular matrix and of a cell to another cell, and form heterodimers consisting of two different subunits, i.e., an α-chain and a β-chain. Recently, attention has been focused on an integrin-associated molecule CD47 (IAP) forming a complex with the αvβ3 integrin, and medical uses of antibodies against it have also been studied.
WO97/32601 attempts to raise a monoclonal antibody against a splenic interstitial cell strain with the purpose of developing a specific antibody capable of identifying splenic interstitial cells and describes the acquisition of a novel monoclonal antibody recognizing mouse CD47 as an antigen. On the other hand, WO97/32601 discloses that said monoclonal antibody has the property of inducing apoptosis in myeloid cells.
WO99/12973 describes monoclonal antibodies raised against CD47 of humans (hereinafter referred to as human CD47; the amino acid sequence and nucleotide sequence described in J. Cell Biol., 123, 485-496, 1993; Journal of Cell Science, 108, 3419-3425, 1995) and having the property of inducing apoptosis in nucleated blood cells having the human CD47 (myeloid cells and lymphocytes), i.e., monoclonal MABL-1 and MABL-2 antibodies, and hybridomas producing them, i.e., MABL-1 (FERM BP-6100) and MABL-2 (FERM BP-6101).
WO02/33072 and WO02/33073 disclose a single chain Fv having a single chain Fv region having the property of inducing apoptosis in nucleated blood cells having the human CD47 from a monoclonal antibody raised against the human CD47.
However, when monoclonal antibodies raised against human CD47 are to be used as therapeutic agents, it is necessary to lower the antigenicity while retaining the CD47-binding activity and apoptosis-inducing activity.